The quest for safer and more effective vaccines has taken on a sudden urgency with the very real threat of bioterrorism. Only a handful of vaccines covering a small proportion of potential biowarfare agents are available (e.g. anthrax and smallpox) and even these suffer from extremely poor safety profiles. Therefore, next generation vaccines for these and many other category A-C pathogens with improved safety and the capacity to induce more rapid, more potent and broader protection are needed. As part of our ongoing efforts to develop improved vaccines for a variety of bacterial and viral pathogens, we are developing novel and powerful vaccine delivery and adjuvant platforms that efficiently target the innate immune response. These platforms are ideally suited to meet many of the new challenges of biodefense vaccines. Specifically, we propose to use a powerful drug discovery engine aimed at identifying small molecule immune potentiators (SMIPs) and then optimizing their therapeutic indices through a reiterative hit-to-lead process. Lead compounds will be tested as adjuvants for subunit vaccines against category A-C pathogens in combination with microparticle delivery systems developed at Chiron. Our initial focus will be on enhancing the immunogenicity of recombinant protective antigen (rPA) from B. anthracis due to the fact that this is a well characterized antigen for a category A pathogen with an established record in challenge models. This will be done by first formulating rPA with our existing delivery systems and synthetic MPL derivatives to evaluate the general performance of these novel formulations in immunogenicity/ protection studies (Aim 1). Then in combination with our SMIP discovery efforts (Aim 2), optimized adjuvant-delivery formulations of rPA will be evaluated in animal models (Aim 3). Due to the flexibility of our platforms, other more experimental vaccine candidates such as capsular antigen for anthrax and candidate antigens for other potential bioterrorism agents (e.g.Y. pestis) will also be evaluated after proof of concept is achieved with the optimal adjuvant-delivery system combination for rPA. These efforts meet the near term needs for more effective and safer biodefense vaccines and set the foundation for improved innate immune-based therapies of the future through our SMIP design and discovery program.